Facon T et al. Proc ASH 2013;Abstract 2.

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Facon T et al. Proc ASH 2013;Abstract 2. Initial Phase 3 Results of the First (Frontline Investigation of Lenalidomide + Dexamethasone versus Standard Thalidomide) Trial (MM-020/IFM 07 01) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Stem Cell Transplantation (SCT) Facon T et al. Proc ASH 2013;Abstract 2.

Background Melphalan/prednisone/thalidomide (MPT) is a standard therapy for patients with newly diagnosed multiple myeloma (NDMM). MPT demonstrated a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) compared to MP (Blood 2011;118(5):1239). The combination of lenalidomide (R) with low-dose dexamethasone increased OS with reduced toxic effects compared to R in combination with high-dose dexamethasone in NDMM (Lancet Oncol 2010;11(1):29). Study objective: To determine the efficacy and safety of R in combination with low-dose dexamethasone (Rd) compared to MPT in transplant-ineligible patients with NDMM. Facon T et al. Proc ASH 2013;Abstract 2.

Phase III FIRST Trial Design Rd until progression (n = 535) Eligibility (n = 1,623) Symptomatic NDMM Transplant ineligible or ≥65 years old Renal impairment allowed, but patients requiring dialysis excluded 1:1:1 R Rd for 18 cycles (Rd18) (n = 541) MPT for 12 cycles (n = 547) R: 25 mg d1-21, every 4 weeks d: 40 mg d1, 8, 15, 22, every 4 weeks M: 0.25 mg/kg d1-4, every 6 weeks P: 2 mg/kg d1-4, every 6 weeks T: 200 mg d1-42, every 6 weeks Primary endpoint: PFS Patients were stratified by age, country and ISS stage. Facon T et al. Proc ASH 2013;Abstract 2.

PFS: Intention-to-Treat (ITT) Population Median PFS Rd (n = 535) 25.5 mos Rd18 (n = 541) 20.7 mos MPT (n = 547) 21.2 mos 100 80 60 40 20 Hazard ratio Rd vs. MPT: 0.72; p = 0.00006 Rd vs. Rd18: 0.70; p = 0.00001 Rd18 vs. MPT: 1.03; p = 0.70349 Patients (%) 72 wks 6 12 18 24 30 36 42 48 54 60 Time (months) With permission from Facon T et al. Proc ASH 2013;Abstract 2.

PFS According to Subgroup Hazard ratio (HR) and 95% CI HR (95% Cl) Age > 75 Age ≤ 75 Gender: female Gender: male Asia Europe North America and Pacific ISS stage: I or II ISS stage: III CrCl < 30 ml/min CrCl 30 – 50 ml/min CrCl 50 – 80 ml/min CrCl ≥ 80 ml/min ECOG PS Grade 0 ECOG PS Grade 1 ECOG PS Grade 2 LDH < 200 IU/l LDH ≥ 200 IU/l Cytogenetics High-risk Cytogenetics Non-high Risk ITT patients 0.81 (0.62 - 1.05) 0.68 (0.56 - 0.83) 0.73 (0.58 - 0.93) 0.71 (0.57 - 0.88) 0.61 (0.33 - 1.14) 0.77 (0.63 - 0.93) 0.64 (0.46 - 0.89) 0.70 (0.57 - 0.87) 0.75 (0.59 - 0.95) 0.76 (0.44 - 1.30) 0.66 (0.48 - 0.91) 0.74 (0.58 - 0.95) 0.71 (0.51 - 1.01) 0.54 (0.39 - 0.74) 0.81 (0.65 - 1.01) 0.80 (0.57 - 1.12) 0.69 (0.58 - 0.83) 0.96 (0.66 - 1.39) 1.23 (0.78 - 1.93) 0.69 (0.53 - 0.90) 0.72 (0.61 - 0.85) 0.125 0.25 0.5 1 2 4 8 Favoring Rd Favoring MPT With permission from Facon T et al. Proc ASH 2013;Abstract 2.

Time to Progression and Time to Second Antimyeloma Therapy (AMT) Time to 2nd AMT Median TTP Rd (n = 535) 32.5 mos Rd18 (n = 541) 21.9 mos MPT (n = 547) 23.9 mos Median Time to 2nd AMT Rd (n = 535) 39.1 mos Rd18 (n = 541) 28.5 mos MPT (n = 547) 26.7 mos 100 80 60 40 20 100 80 60 40 20 Patients (%) Patients (%) Hazard ratio Rd vs. MPT: 0.68; p = 0.00001 Rd vs. Rd18: 0.62; p ≤ 0.00001 Rd18 vs. MPT: 1.11; p = 0.21718 Hazard ratio Rd vs. MPT: 0.66; p < 0.00001 Rd vs. Rd18: 0.74; p = 0.00067 Rd18 vs. MPT: 0.88; p = 0.12333 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60 TTP (months) Time to 2nd AMT (months) With permission from Facon T et al. Proc ASH 2013;Abstract 2.

Overall survival (months) Interim Analysis of OS 574 deaths (35% of ITT) 4-year OS Rd (n = 535) 59.4% Rd18 (n = 541) 55.7% MPT (n = 547) 51.4% 100 80 60 40 20 Patients (%) Hazard ratio Rd vs. MPT: 0.78; p = 0.0168 Rd vs. Rd18: 0.90; p = 0.307 Rd18 vs. MPT: 0.88; p = 0.184 6 12 18 24 30 36 42 48 54 60 Overall survival (months) With permission from Facon T et al. Proc ASH 2013;Abstract 2.

Response Rates Response Continuous Rd (n = 535) Rd18 (n = 541) MPT Overall response rate 75.1% 73.4% 62.3% Complete response 15.1% 14.2% 9.3% Very good partial response 28.4% 28.5% 18.8% Partial response 31.6% 30.7% 34.2% Stable disease 18.9% 20.5% 26.5% Time to response: 1.8 mo (continuous Rd); 1.8 mo (Rd18); 2.8 mo (MPT) Duration of response: 35.0 mo (continuous Rd); 22.1 mo (Rd18); 22.3 mo (MPT) Facon T et al. Proc ASH 2013;Abstract 2.

Select Adverse Events Grade 3/4 Continuous Rd (n = 532) Rd18 (n = 540) MPT (n = 541) Anemia 18.2% 15.7% 18.9% Neutropenia 27.8% 26.5% 44.9% Thrombocytopenia 8.3% 8.0% 11.1% Febrile neutropenia 1.1% 3.0% 2.6% Infections 28.9% 21.9% 17.2% Pneumonia 8.1% 5.7% DVT and/or PE 7.9% 5.6% 5.4% Cataract 5.8% 0.6% DVT = deep vein thrombosis; PE = pulmonary embolism Facon T et al. Proc ASH 2013;Abstract 2.

Incidence of Second Primary Malignancy (SPM) Malignancy, n (%) Continuous Rd (n = 532) Rd18 (n = 540) MPT (n = 541) AML 1 (0.2%) 4 (0.7%) MDS 6 (1.1%) MDS to AML 0 (0%) 2 (0.4%) B-cell Solid tumors 15 (2.8%) 29 (5.4%) Invasive SPM 17 (3.2%) 30 (5.6%) 27 (5.0%) Pts with ≥1 noninvasive, nonmyeloma skin cancer 22 (4.1%) 17 (3.1%) 21 (3.9%) AML = acute myeloid leukemia; MDS = myelodysplastic syndromes Facon T et al. Proc ASH 2013;Abstract 2.

Author Conclusions Continuous administration of Rd significantly extended PFS, with an OS benefit in comparison to MPT. PFS results: Hazard ratio = 0.72; p = 0.00006 Consistent benefit across most patient subgroups Continuous Rd was better than Rd18 Hazard ratio = 0.70; p = 0.00001 Planned interim OS results: Hazard ratio = 0.78; p = 0.0168 Rd was superior to MPT across all efficacy secondary endpoints. The safety profile with continuous Rd was manageable. In transplant-ineligible patients with NDMM, the FIRST trial establishes continuous Rd as a new standard. Facon T et al. Proc ASH 2013;Abstract 2.

FIRST: A Phase III Trial of Continuous Rd versus Rd18 versus MPT for Patients with NDMM Two questions were being asked: Is Rd better than MPT, and does continuous therapy improve the benefit of Rd over MPT? In terms of PFS, OS and time to second antimyeloma therapy, continuous Rd is clearly the winner. The time to progression (TTP) curve is similar for MPT and Rd when they are administered for equal durations. The SPM rate was lower with continuous Rd than in the other 2 groups. These data support the importance of continuous therapy in multiple myeloma whether patients are older, as in this trial, or younger, as in the post- transplant period. In terms of OS, it is important that continuous Rd was statistically different from MPT but not from Rd18. The difference in TTP between continuous Rd and Rd18 is big. I believe that the only way for a big OS difference to occur in an induction trial is if 1 of the arms is inferior, because patients are living so long. We probably don’t have enough follow-up yet to see a difference in survival between continuous Rd and Rd18. Clearly Rd is better than MPT, and one wouldn’t administer MPT for longer than the duration used in this trial. The biggest issue regarding this study is that few US physicians administer MPT. It’s hard to understand what the extrapolation of this data is for similar patients in the United States. Interview with Sagar Lonial, MD, January 22, 2014